PROJECT SUMMARY/ABSTRACT The Cancer Prevention Program (CPP) is a new program that integrates the previous Behavioral and Health Disparities Research and Clinical Cancer Prevention programs to focus on interventional cancer prevention research. The CPP consists of 49 members from 17 departments and is led by Dr. Powel Brown, who focuses on cancer prevention clinical trials, and 2 co-leaders: Dr. Paul Cinciripini, an expert in smoking cessation, and Dr. Karen Basen-Engquist, who has pioneered exercise and weight-management interventions. The overarching goal of the CPP is to develop cancer prevention interventions and improve health in individuals at risk for cancer and in cancer survivors. Three specific aims support this primary objective. In Aim 1, we will discover biological pathways critical for cancer development and target these pathways in preclinical models. In Aim 2, we will discover critical psychobiological, social, and conditional/situational determinants and predictors of cancer risk behavior to inform future cancer preventive interventions. In Aim 3, we will develop and test novel therapeutic and behavioral interventions in clinical and community-based trials to reduce cancer risk and promote health in individuals at risk for cancer and cancer survivors. Thirty-five CPP members have annual direct peer- reviewed funding of $12.8M, with $6.2M (48%) from the NCI. CPP members have authored more than 1322 published papers (20% intra-programmatic, 44% inter-programmatic, and 73% external collaborations), of which 31% appeared in journals with IF >5 and 10% appeared in journals with IF >10, including CA Cancer J Clin, N Engl J Med, Lancet, JAMA, and Nature. Members have conducted research that used all 14 of the shared resources. Major accomplishments include the demonstration that ARID1A loss is a common early oncogenic event leading to PARP inhibitor sensitivity and the identification of oncogenic changes in precancerous polyps in patients with hereditary colon cancer syndromes (Aim 1), the discovery of a neural EEG biomarker of reward sensitivity that predicts smoking cessation (Aim 2), and the discovery that varenicline is superior to bupropion in reducing depressive symptoms while quitting and promoting smoking cessation for smokers with low reward sensitivity (Aim 3). Major multi-investigator prevention projects include an NCI-funded preclinical consortium (PREVENT), an NCI-funded clinical cancer prevention consortium (N01 Chemoprevention Consortium), 2 Tobacco Centers of Regulatory Science programs, a U54 to study a genetically informed biomarker (nicotine metabolite ratio) for smoking cessation, and an NRG R01 study of ovarian cancer biomarker modulation by activity and diet. Future goals are to target early oncogenic drivers in cancer prevention trials, develop immune- based cancer prevention strategies, combine energy balance and drug-based prevention strategies, develop adaptive smoking cessation treatment algorithms to assign smokers to pharmacotherapy with the goal of changing clinical practice, and reduce cancer incidence and mortality in Houston, the nation, and the world.